Project Summary Molecular imaging provides the means to quantitatively study many types of processes in the human brain in a minimally invasive manner. However, the complexity of the brain results in many instances in which it is desirable to be able to study more than one property simultaneously, such as measuring neuroreceptor binding at the same time as transporters or cerebral perfusion together with receptor occupancy. While one option for doing so in some cases may be to use multiple modalities (e.g. PET/MR), if the measurements are to be done with similar sensitivity, spatial resolution, and temporal resolution, then the ability to image multiple probes using a single modality is beneficial. Because SPECT utilizes tracers labeled with radionuclides that emit gamma rays at specific energies, it is often touted for its possibility of imaging multiple radiotracers simultaneously. However, multi-tracer SPECT studies are rarely done in practice due to the limited energy resolution of conventional gamma cameras that necessitates complicated correction schemes to account for crosstalk between the different energy channels. High-purity germanium (HPGe) detector technology provides an order of magnitude improvement in energy resolution over conventional sodium iodide-based gamma cameras, allowing for easy separation of relevant radionuclide photopeaks (e.g. 140 keV for 99mTc and 159 keV for 123I) and the use of narrow energy windows that significantly reduces scatter. We previously have demonstrated the applicability of mechanically-cooled HPGe detectors to SPECT and here propose to pursue further improvements in the technology, including increased crystal size and improved intrinsic spatial resolution. The use of modular cameras facilitates the design of application-specific SPECT systems with good spatial resolution, sensitivity, and angular sampling. We will design a brain-specific SPECT system capable of making simultaneous, quantitative measurements of two or more molecular probes based on the improved HPGe detector technology. In parallel with the detector developments we will demonstrate the multi-tracer methodology through non-human primate SPECT scans that will be acquired using a two-camera prototype system. We will utilize analytical, simulation, and experimental studies in developing a design for a SPECT system for human brain imaging offering unprecedented capabilities for multi-tracer studies.